Viral respiratory infections are the major cause of asthma exacerbations. Of the respiratory viruses that precipitate these attacks of asthma, RV is the most frequent. Based upon studies with in vitro models and RV16 inoculation studies of subjects with asthma, evidence shows that RV infection of airway cells generates pro-inflammatory cytokines, i.e., IL-8. The in vivo inoculation of allergic and asthmatic subjects with RV16 generates IL-8, relates to neutrophil recruitment to the airway, and, in some subjects, is associated with increases in airway responsiveness. Finally, there is preliminary evidence that the IFN-gamma generation to RV is reduced in some subjects with asthma, and the dysregulation of this cytokine response relates to the severity of the respiratory infection and time to virus clearance from the airway. Consequently, we now hypothesize that a major risk factor for asthma exacerbations with RV respiratory infections is a diminished IFN-gamma response to this virus. It is further hypothesized that diminished IFN-gamma production to RV determines the likelihood for RV to extend to the lower airway, provoke inflammation and thus exacerbate asthma. To test this hypothesis, three specific aims are established. Specific Aim 1 will test the hypothesis that dysregulation of the immune response relates to the development of lower airway infection and inflammation. To accomplish this hypothesis, two groups of asthmatic subjects will be selected for study, one with a high peripheral blood mononuclear cell (PBMC) generation of IFN-gamma to RV and, the other, a low response. These subjects will undergo experimental RV16 inoculation and the host's response to infection will be evaluated in relationship to cold symptoms, changes in pulmonary physiology, bronchial inflammation and infection as detected in sputum or airway mucosal biopsy and generation of the cytokines/chemokines. Specific Aim 2 will determine the mechanisms of IFN-gamma production in response to RV by identifying the cell source, nature of IFN-gamma-inducing factors, and the cell source for IFN-gamma inducing factors. Specific Aim 3 will test the hypothesis that asthma exacerbations to a natural RV infection are related to a cytokine dysregulated response to RV. Subjects with and without an exacerbation of asthma from a natural cold will be evaluated as described in Specific Aim 1. The results from these studies may provide a new insight into the importance and mechanisms of the asthmatic subject's immune IFN-gamma production and its relationship to asthma exacerbations.